Abnormal conditions or the prostate constitute a major medical problem in the United States. Prostatitis, benign enlargement (BPH), and malignant growth of the prostate (CaP), will effect the lives of most men over the age of 50. BPH is a bothersome abnormal growth that fortunately is readily treated by a variety of options. Prostate cancer, if detected early is curable. However, metastatic disease can be fatal, as there is currently no available curative therapy for metastatic prostate cancer. In addition, because of the extreme heterogeneity with regard to the biologic potential of prostatic cancer, there is debate on the approach to therapy, even with localized disease. There is a lack of consensus and viable approaches to management and therapy for CaP. This reflects our lack of knowledge regarding the biologic determinants responsible for this spectrum of behavior at a level that would provide appropriate therapeutic intervention. This O'Brien Urology Center project will focus its attention on determining changes in the cellular phenotype that is associated with disease progression from normal to premalignant lesions, to localized cancer, and to distant disseminated disease. In this project we will center on three areas related to cellular signaling and cell cycle programming as it related to benign and malignant prostate growth. The first project will focus its research efforts on cell cycle regulation in prostate cancer progression. The second project will examine alterations in PKC isozyme signaling in metastatic progression and in apoptotic cell death. The third project will examine the role of PSM antigen as a folate hydrolase in the biology of the prostate and its evolution to cancer. These projects and the recruitment of developmental programs to the Center are designed to provide an understanding of the biology of progression of CaP and developing strong rational for innovative interventional strategies.